Original Research ajog.

org

OBSTETRICS
Impact of new definitions of preeclampsia at term on
identification of adverse maternal and perinatal outcomes
Jonathan Lai, MD; Argyro Syngelaki, PhD; Kypros H. Nicolaides, MD; Peter von Dadelszen, MD, DPhil; Laura A. Magee, MD

BACKGROUND: Any definition of preeclampsia should identify women
and babies at greatest risk of adverse outcomes.
OBJECTIVE: This study aimed to investigate the ability of the American
College of Obstetricians and Gynecologists and International Society for the Study
of Hypertension in Pregnancy definitions of preeclampsia at term gestational age
(
37 0/7 weeks) to identify adverse maternal and perinatal outcomes.
STUDY DESIGN: In this prospective cohort study at 2 maternity hospitals
in England, women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks’
gestation underwent assessment that included history; ultrasonographic
estimated fetal weight; Doppler measurements of the pulsatility index in the
uterine, umbilical, and fetal middle cerebral arteries; and serum placental
growth factoretoesoluble fms-like tyrosine kinase-1 ratio. Obstetrical records
were examined for all women with chronic hypertension and those who
developed new-onset hypertension, with preeclampsia (de novo or super-
imposed on chronic hypertension) defined in 5 ways: traditional, based on
new-onset proteinuria; American College of Obstetricians and Gynecologists
2013 definition; International Society for the Study of Hypertension in Preg-
nancy maternal factors definition; International Society for the Study of Hy-
pertension in Pregnancy maternal factors plus fetal death or fetal growth
restriction definition, defined according to the 35 0/7 to 36 6/7 weeks’
gestation scan as either estimated fetal weight <3rd percentile or estimated
fetal weight at the 3rd to 10th percentile with any of uterine artery pulsatility
index >95th percentile, umbilical artery pulsatility index >95th percentile, or
middle cerebral artery pulsatility index <5th percentile; and International
Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus
angiogenic imbalance definition, defined as placental growth factor <5th
percentile or soluble fms-like tyrosine kinase-1etoeserum placental growth
factor >95th percentile. Detection rates for outcomes of interest (ie, severe
maternal hypertension, major maternal morbidity, perinatal mortality or major
neonatal morbidity, neonatal unit admission
48 hours, and birthweight
<10th percentile) were compared using the chi-square test, and P<.05 was
considered significant.
RESULTS: Among 15,248 singleton pregnancies, the identification of
women with preeclampsia varied by definition: traditional, 15 of 281 (1.8%;
248); American College of Obstetricians and Gynecologists, 15 of 326 (2.1%;
248); International Society for the Study of Hypertension in Pregnancy maternal
factors, 15 of 400 (2.6%; 248); International Society for the Study of Hyper-
tension in Pregnancy maternal-fetal factors, 15 of 434 (2.8%; 248); and In-
ternational Society for the Study of Hypertension in Pregnancy maternal-fetal
factors plus angiogenic imbalance, 15 of 500 (3.3%; 248). Compared with the
traditional definition of preeclampsia, the International Society for the Study of
Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance
best identified the adverse outcomes: severe hypertension (40.6% [traditional]
vs 66.9% [International Society for the Study of Hypertension in Pregnancy
maternal-fetal factors plus angiogenic imbalance, P<.0001], 59.2% [Inter-
national Society for the Study of Hypertension in Pregnancy maternal-fetal
factors, P¼.004], 56.2% [International Society for the Study of Hypertension
in Pregnancy maternal factors, P¼.013], 46.1% [American College of Ob-
stetricians and Gynecologists, P¼.449]); P<.0001); composite maternal
severe adverse event (72.2% [traditional] vs 100% for all others; P¼.046);
composite of perinatal mortality and morbidity (46.9% [traditional] vs 71.1%
[International Society for the Study of Hypertension in Pregnancy maternal-fetal
factors plus angiogenic imbalance, P¼.002], 62.2% [International Society for
the Study of Hypertension in Pregnancy maternal-fetal factors, P¼.06], 59.8%
[International Society for the Study of Hypertension in Pregnancy maternal
factors, P¼.117], 49.4% [American College of Obstetricians and Gynecolo-
gists, P¼.875]); neonatal unit admission for
48 hours (51.4% [traditional] vs
73.4% [International Society for the Study of Hypertension in Pregnancy
maternal-fetal factors plus angiogenic imbalance, P¼.001], 64.5% [Interna-
tional Society for the Study of Hypertension in Pregnancy maternal-fetal factors,
P¼.070], 60.7% [International Society for the Study of Hypertension in
Pregnancy maternal factors, P¼.213], 53.3% [American College of Obste-
tricians and Gynecologists, P¼.890]); birthweight <10th percentile (40.5%
[traditional] vs 78.7% [International Society for the Study of Hypertension in
Pregnancy maternal-fetal factors plus angiogenic imbalance, P<.0001],
70.1% [International Society for the Study of Hypertension in Pregnancy
maternal-fetal, P<.0001], 51.3% [International Society for the Study of Hy-
pertension in Pregnancy maternal factors, P¼.064], 46.3% [American College
of Obstetricians and Gynecologists, P¼.349]).
CONCLUSION: Our findings present an evidence base for the broad
definition of preeclampsia. Our data suggest that compared with a
traditional definition, a broad definition of preeclampsia can better identify
women and babies at risk of adverse outcomes. Compared with the
American College of Obstetricians and Gynecologists definition, the more
inclusive International Society for the Study of Hypertension in Pregnancy
definition of maternal end-organ dysfunction seems to be more sensitive.
The addition of uteroplacental dysfunction to the broad definition optimizes
the identification of women and babies at risk, particularly when angio-
genic factors are included.
Key words: angiogenic markers, definition, outcomes, preeclampsia,
ultrasound

Cite this article as: Lai J, Syngelaki A, Nicolaides KH,
et al. Impact of new definitions of preeclampsia at term on
identification of adverse maternal and perinatal out-
comes. Am J Obstet Gynecol 2021;224:518.e1-11.
0002-9378/free
ª 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2020.11.004
Introduction
Preeclampsia (PE) complicates 2% to 4%
of pregnancies worldwide,1,2 with most
occurring at term gestational age (
37 0/
7 weeks). The traditional definition of PE
is based on the development of hyper-
tension and proteinuria.
PE is distinguished from other hy-
pertensive disorders of pregnancy,
namely, chronic and gestational hyper-
tension, based on its greater risk of
adverse maternal and perinatal

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This 35 0/7 to 36 6/7 weeks’ gestation

AJOG at a Glance visit included the following: recording of
Why was this study conducted? maternal demographics and medical
This study aimed to investigate the ability of different definitions of preeclampsia history; ultrasound examination for fetal
(PE) at term gestational age (
37 0/7 weeks) to identify adverse maternal and anatomy and estimated fetal weight
perinatal outcomes. (EFW) from measurements of fetal head
circumference, abdominal circumfer-
Key findings ence, and femur length15,16 and Doppler
Compared with the traditional definition of PE, a broad definition significantly measurements of the pulsatility index
improved the detection of adverse outcomes for mothers and babies, owing to the (PI) in the uterine artery (UtA), umbil-
addition of less abnormal platelet, creatinine, and liver enzyme results but ical artery (UA), and fetal middle cere-
particularly associated with the addition of uteroplacental dysfunction based on bral artery (MCA); and measurement of
an objective assessment of fetal growth restriction and angiogenic markers. maternal serum placental growth factor
(PlGF) and soluble fms-like tyrosine
What does this add to what is known? kinase-1 (sFlt-1) by an automated
These data contribute to the evidence base for use of a broad definition of PE that biochemical analyzer (BRAHMS KRYP-
includes uteroplacental dysfunction at term. TOR compact PLUS; Thermo Fisher
Scientific, Hennigsdorf, Germany).
outcomes. However, it is well recognized that adopted the ISSHP definition.14 Gestational age was determined by the
that many women with chronic or However, controversy remains, con- measurement of fetal crown-rump
gestational hypertension still suffer from cerning how maternal end-organ length at 11 to 13 weeks’ gestation or
complications typically associated with dysfunction should be defined, whether the fetal head circumference at 19 to 24
PE. For example, many women with uteroplacental dysfunction should be weeks’ gestation.17,18
gestational hypertension suffer end- included in the diagnostic criteria for PE, The inclusion criteria for this analysis
organ complications, such as pulmo- and, if so, how should uteroplacental were singleton pregnancies that deliv-
nary edema,3 and those with severe hy- dysfunction be defined. ered a nonmalformed live-born or still-
pertension more frequently experience Any definition of PE should optimally born baby. We excluded pregnancies
adverse outcomes (compared with identify women and babies at increased with aneuploidies and major fetal
women with traditionally defined PE), risk of adverse outcomes. The objective abnormalities.
such as placental abruption, preterm of this study was to investigate the ability
delivery, perinatal death, small-for- of different definitions of PE at term Diagnosis of preeclampsia
gestational-age (SGA) infants, and gestational age to identify adverse Data related to pregnancy outcome were
neonatal respiratory distress syndrome maternal and perinatal outcomes. We collected from the hospital maternity
(RDS).4,5 Among women with chronic compared the traditional definition of records or those of their general medical
hypertension, the traditional definition PE (established clinical standard), practitioners. The obstetrical records of
of superimposed PE accounts for fewer ACOG definition (maternal criteria all women with chronic hypertension
than 50% of preterm births and a mi- only), and ISSHP definition (maternal and those with new-onset, pregnancy-
nority of SGA infants and high-level and/or uteroplacental criteria), consid- associated hypertension were examined
neonatal care admissions.6e10 ering the definitions of uteroplacental to determine the diagnosis of gestational
To better reflect the risk of adverse dysfunction that incorporated fetal hypertension or PE.
pregnancy complications among women growth restriction (FGR) and the mea- Gestational hypertension was defined
with a hypertensive disorder of preg- surements of angiogenic markers. as new-onset hypertension (ie, systolic
nancy, the definition of PE has been blood pressure [BP] of
140 mm Hg or
revised to include cases without pro- Methods diastolic BP of
90 mm Hg, on at least 2
teinuria but with evidence of other Study design and participants occasions, 4 hours apart) that developed
maternal end-organ or uteroplacental This was a prospective cohort study of after 20 weeks’ gestation, in a previously
dysfunction. This “broad” definition has women who attended a routine hospital normotensive woman.19
now been adopted by most national and visit at 35 0/7 to 36 6/7 weeks’ gestation In this study, 5 definitions of PE were
international clinical practice guidelines, at King’s College Hospital, London, and considered (Supplemental Table), based
notably the American College of Ob- Medway Maritime Hospital, Gillingham, on the finding of an additional feature (ie,
stetrics and Gynecology (ACOG),11,12 United Kingdom, between October 2016 a maternal end-organ dysfunction, with
the International Society for the Study and September 2018. The women gave or without uteroplacental dysfunction,
of Hypertension in Pregnancy written informed consent to participate depending on the definition) among
(ISSHP),13 and, most recently, the Na- in the study, which was approved by the women with chronic hypertension or in
tional Institute for Health and Care National Health Service Research Ethics association with new-onset hypertension
Excellence (NICE), United Kingdom, Committee. among other women (as defined above).

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We included only quantitative measures

TABLE 1
of renal, hepatic, or hematologic
Baseline characteristics and outcomes of the screening population
dysfunction, according to the ACOG and
ISSHP criteria.12,19 Characteristic Pregnancies (N¼15,248)
The traditional definition of PE was Maternal demographics
based on new-onset proteinuria (ie,
Age (y) 32.2 (28.3e35.8)

300 mg/24 h or protein-to-creatinine
2
ratio of
30 mg/mmol or
2þ on BMI (kg/m ) 29.0 (26.1e32.7)
dipstick testing).20 BMI>30 kg/m 2
6447.0 (42.2)
The ACOG definition of PE was based Weight (kg) 79.0 (71.0e89.9)
on the development of at least 1 of the
Height (cm) 165.0 (161.0e170.0)
following: new-onset proteinuria, renal
insufficiency (ie, serum creatinine of Racial origin
>97 mmol/L) in the absence of under- White 12,125 (79.5)
lying renal disease, hepatic involvement Black 1688 (11.1)
with serum transaminases more than
South Asian 680 (4.5)
twice the upper limit of normal (ie,
65
IU/L for our laboratory), thrombocyto- East Asian 316 (2.1)
penia (ie, platelet count of <100,000/ Mixed 439 (2.9)
mL), neurologic complications (ie, Cigarette smoker 963 (6.3)
headache or visual symptoms), or pul-
Family history
monary edema.12
The ISSHP definition of PE was Mother had PE 569 (3.7)
examined according to its maternal Medical history
(ISSHP maternal factors [ISSHP-M]) Chronic hypertension 147 (1.0)
and uteroplacental components (ISSHP
maternal-fetal factors [ISSHP-MF]). The On antihypertensive medication 119 (81.0)
ISSHP-M definition was based on at least Systemic lupus erythematosus or antiphospholipid 36 (0.2)
1 of the following: new-onset protein- antibody syndrome
uria, renal insufficiency (serum creati- Diabetes mellitus (type 1 or 2) 148 (1.0)
nine of
90 mmol/L) in the absence of Obstetrical history
underlying renal disease, hepatic
Nulliparous 7122 (46.7)
involvement with serum transaminases
of >40 IU/L, thrombocytopenia (ie, Parous without previous PE 7857 (51.5)
platelet count of <150,000/mL), or Parous with previous PE 269 (1.8)
neurologic complications (ie, altered Interpregnancy interval (y) 2.8 (1.8e4.7)
mental status, blindness, stroke, clonus,
This pregnancy
severe headaches, and persistent visual
scotomata); the criteria for altered Conception
mental status and clonus were not Natural 14,584 (95.6)
available. The ISSHP-MF definition Assisted by use of ovulation drugs 87 (0.6)
included all criteria as above for ISSHP-
In vitro fertilization 577 (3.8)
M, with the addition of fetal death or
FGR; FGR was defined according to the Gestational age at screening (wk) 36.1 (35.9e36.4)
findings of the 35 0/7 to 36 6/7 weeks’ Gestational diabetes mellitus a
636 (4.2)
gestation scan, as either EFW <3rd Screening markers for PE at 35 0/7 to 36 6/7 wk
percentile or EFW at the 3rd to 10th
Mean arterial pressure (mm Hg) 88.1 (83.2e93.2)
percentile in the presence of either of the
following: UtA-PI >95th percentile, UA- Systolic BP (mm Hg) 118.5 (111.8e125.0)
PI >95th percentile, or MCA PI <5th Systolic BP
140 mm Hg 221 (1.4)
percentile. The ISSHP-MF-AI definition Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021. (continued)
included all criteria as above for ISSHP-
MF, with the addition of angiogenic
imbalance, defined as serum PlGF <5th Outcome measures severe maternal hypertension, a com-
percentile or sFlt-1etoePlGF ratio The outcomes of interest were major posite of maternal death or major
>95th percentile. maternal and perinatal outcomes: morbidity, a composite of perinatal

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diastolic BP of
110 mm Hg. Major

TABLE 1 maternal morbidity was defined as 1 or
Baseline characteristics and outcomes of the screening population (continued) more of eclampsia, blindness, stroke,
Characteristic Pregnancies (N¼15,248) myocardial ischemia, pulmonary edema,
Diastolic BP (mm Hg) 73.0 (68.3e78.0)
elevated liver enzymes, hepatic hema-
toma, low platelets, or acute kidney
Diastolic BP
90 mm Hg 256 (1.7) injury; morbidity was based on the core
Uterine artery PI 0.7 (0.6e0.8) maternal outcome set in PE, with the
Uterine artery PI >95th percentile 1068 (6.8) exception of liver rupture, postpartum
Umbilical artery PI 0.91 (0.8e1.01)
hemorrhage, intensive care unit admis-
sion, and intubation and ventilation (not
Umbilical artery PI >95th percentile 435 (2.9) for childbirth) that were not available,
Middle cerebral artery PI 1.75 (1.54e1.92) placental abruption that was defined
Middle cerebral artery PI >95th percentile 521 (3.4) clinically and underreported, and the
PlGF (pg/mL) 251.0 (132.6e467.6) addition of myocardial ischemia based
on the Delphi-derived preeclampsia in-
PlGF <5th percentile 762 (5.0)
tegrated estimate of risk score.21,22
sFlt-1etoePlGF ratio 8.3 (3.6e21.5) Neonatal death was considered up to
sFlt-1etoePlGF ratio >95th percentile 762 (5.0) 28 days after birth. Major neonatal
sFlt-1etoePlGF ratio >95th percentile or 1008 (6.6) morbidity was defined as 1 or more of
PlGF <5th percentile the following, as indicated in the
BadgerNet Neonatal discharge sum-
Pregnancy outcomes
mary: ventilation (ie, need for contin-
Gestational age at birth (wk) 40.0 (39.1e40.9) uous positive airway pressure or nasal
Induction of labor 3253 (21.3) continuous positive airway pressure or
Vaginal delivery 11,187 (73.4) intubation), RDS (the need for surfac-
tant and ventilation), brain injury (ie,
Spontaneous vaginal delivery 8849 (58.0)
hypoxic-ischemic encephalopathy,
Cesarean delivery 4062 (26.6) intraventricular hemorrhage grade
2,
b
Perinatal mortality or major morbidity 697 (4.6) or periventricular leukomalacia), sepsis
Intrauterine fetal death 33 (0.2) (based on positive blood cultures),
anemia treated with blood transfusion,
Neonatal death 1 (0.006)
or necrotizing enterocolitis requiring
Ventilation 147 (1.0) surgical intervention. The birthweight
RDS 230 (1.5) percentile for gestational age was
Brain injury 32 (0.2) determined using the Fetal Medicine
Foundation fetal and neonatal weight
Sepsis 518 (3.4)
medical records.23 Perinatal outcomes
Anemia 12 (0.1) covered the core perinatal outcome set
NEC 1 (0.006) in PE, with the exception of neonatal
Neonatal unit admission
48 h 1086 (7.1) seizures.
Birthweight <10th percentilec 1585 (10.4)
Statistical analysis
Data are presented as number (percentage) or median (interquartile range).
Data were summarized descriptively for
BMI, body mass index; BP, blood pressure; NEC, necrotizing enterocolitis requiring surgery; PE, preeclampsia; PI, pulsatility
index; PlGF, placental growth factor; RDS, respiratory distress syndrome requiring surfactant; sFlt-1, soluble fms-like tyrosine the total population and for different
kinase-1. definitions of PE, with the associated
Adapted from Nicolaides et al.23 impact on gestational hypertension also
a
Gestational diabetes was defined as hyperglycemia diagnosed in pregnancy; b Major neonatal morbidity was defined as 1 or presented. Median and interquartile
more of the following: ventilation, RDS, brain injury, sepsis, anemia, or NEC; c The birthweight percentile for gestational age
was determined using the Fetal Medicine Foundation fetal and neonatal weight medical records. range was used for continuous variables
Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021. and number (percentage) for categori-
cal variables. Comparisons of the
occurrence of adverse maternal and
death or major morbidity (ie, intra-
48 hours, and birthweight <10th perinatal outcomes according to defi-
uterine fetal death, neonatal death to percentile. nitions of PE relative to the traditional
hospital discharge, or neonatal Severe maternal hypertension was one were performed using the chi-
morbidity), neonatal unit admission for defined as systolic BP of
160 mm Hg or square test.

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Results
TABLE 2
Study participants The elements of the preeclampsia definitions for women with new-onset
Table 1 summarizes the maternal and hypertension and those with a history of chronic hypertension
pregnancy characteristics of the study
population and details of the screening New-onset Chronic
marker results and pregnancy outcomes. Characteristic hypertension (n¼741) hypertension (n¼147)
On average, women were in their early Proteinuriaa 270 (3.6) 11 (7.5)
30s and overweight. Most of the women Maternal symptomsb
were white. Few women were cigarette
Headache 21 (2.8) 0
smokers. Very few women reported that
their mothers had PE. Medical history Visual symptoms 20 (2.7) 0
was usually unremarkable, with few Maternal signs c

women reporting chronic hypertension Eclampsia 4 (0.5) 0

(most of which was treated with anti-
Myocardial ischemia 1 (0.1) 0
hypertensive therapy), gestational dia-
betes mellitus, or rheumatic disease. Pulmonary edema 2 (0.3) 0
Most conceptions were natural, and just Abnormal maternal laboratory tests d

over half of the women were parous, Platelet count<150109/L 78 (10.3) 7 (4.8)
with few of them (269 of 8126 [3.3%])
reporting a previous pregnancy compli- Platelet count<100109/L 12 (1.7) 1 (0.7)
cated by PE. The assessment occurred at Serum creatinine
90 mmol/L 23 (3.1) 2 (1.4)
a median of 36 weeks at which point Serum creatinine>97 mmol/L 22 (3.0) 1 (0.7)
<2% of women had elevated BP, and AST or ALT>40 IU/L 96 (13.0) 9 (6.1)
<10% had abnormal readings of UtA,
AST or ALT
65 IU/L 54 (7.3) 0
UA, or MCA PI or abnormal PlGF or
sFlt-1etoePlGF ratio. Birth occurred at Uteroplacental dysfunction
a median of 40.0 weeks, for z20% of Intrauterine fetal death 2 (0.3) 0
women following induction and for EFW <3rd percentile 32 (4.3) 4 (2.7)
z25% overall by cesarean delivery.
EFW at the 3rd to 10th percentile 10 (1.3) 3 (2.0)
Preeclampsia definitions with abnormal Dopplerse
Table 2 presents the elements of the PE Abnormal angiogenic markers 214 (28.9) 15 (10.2)
definitions for women with new-onset at screeningf
(n¼741) or chronic hypertension ACOG, American College of Obstetricians and Gynecologists; ALT, alanine aminotransferase; AST, aspartate aminotransferase;
EFW, estimated fetal weight; ISSHP, International Society for the Study of Hypertension in Pregnancy, PI, pulsatility index; PlGF,
(n¼147). Most commonly, women placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1.
satisfied maternal diagnostic criteria for a
Proteinuria was defined as
2þ by urinary dipstick testing,
30 mg/mmol or 0.3 mg/dL by protein-to-creatinine ratio, or
PE based on abnormal routine labora-
0.3 g/d by 24-hour urine collection; b Headache was defined by the ACOG as new-onset headache unresponsive to
medications and not accounted for by alternative diagnoses, whereas the ISSHP defined headache as “severe”; visual
tory tests (ie, low platelet count or symptoms were not defined by the ACOG but were defined by the ISSHP as persistent visual scotomata; c No information was
elevated liver enzymes) or proteinuria available on altered mental status or clonus. There were no cases of blindness; d No information was available on
disseminated intravascular coagulation or hemolysis; e Abnormal Dopplers were defined as any of the following: uterine artery
specifically among women with chronic PI >95th percentile, umbilical artery PI >95th percentile, or middle cerebral artery PI <5th percentile; f Abnormal angiogenic
hypertension. Most women satisfied markers were defined as PlGF <5th percentile or sFlt-1etoePlGF ratio >95th percentile.
uteroplacental diagnostic criteria based Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021.

on abnormal angiogenic markers at 35 0/

7 to 36 6/7 weeks’ gestation.
Performance of each classification
Table 3 summarizes the number of
women with gestational hypertension
and PE, according to each PE definition
and the associated occurrence of adverse
maternal and perinatal outcomes. PE
was least common with the traditional
definition (1.8%) and become progres-
sively more common, reaching its high-
est value with the ISSHP-MF-AI
definition (3.3%). Most of the increase
was attributable to fewer women being
diagnosed with gestational hyperten-
sion, although some women were clas-
sified as having PE superimposed on
chronic hypertension, particularly with
the move to the ISSHP definitions. Each
definition of PE was associated with a
similar prevalence of adverse maternal
and perinatal outcomes that reflected a
high-risk population. For all definitions,
severe hypertension occurred in just
under 20% of women, and major
maternal morbidity was approximately
5%, most commonly because of hemo-
lysis, elevated liver enzyme levels, and
low platelet count, followed by
eclampsia. At least two-thirds of women
with PE were induced and 40% delivered
by cesarean delivery, whereas just over
half of women with gestational hyper-
tension were induced and about one-
third delivered by cesarean delivery.
Perinatal death or major morbidity
occurred in z9% of pregnancies with

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TABLE 3
Adverse pregnancy outcomes according to the definitions of gestational hypertension and PE
Traditional ACOG ISSHP-M ISSHP-MF ISSHP-MF-AI
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Outcome n¼471 (3.1) n¼281 (1.8) n¼427 (2.8) n¼326 (2.1) n¼367 (2.4) n¼400 (2.6) n¼338 (2.2) n¼434 (2.8) n¼279 (1.8) n¼500 (3.3)
Superimposed on CH — 11 (3.9) — 12 (3.7) — 26 (6.5) — 31 (7.1) — 38 (7.6)
Maternal
Severe hypertension 76 (16.1) 52 (18.5) 69 (16.2) 59 (18.1) 57 (15.5) 73 (18.3) 53 (15.6) 77 (17.7) 43 (15.4) 87 (17.4)
Major morbidity 5 (1.1) 13 (4.6) 0 18 (5.5) 0 18 (4.5) 0 18 (4.1) 0 18 (3.6)
Death 0 1 (0.4) 0 1 (0.3) 0 1 (0.3) 0 1 (0.2) 0 1 (0.2)
Eclampsia 0 4 (1.4) 0 4 (1.2) 0 4 (1.0) 0 4 (0.9) 0 4 (0.8)
Myocardial ischemia 0 1 (0.4) 0 1 (0.3) 0 1 (0.3) 0 1 (0.2) 0 1 (0.2)
Pulmonary edema 0 2 (0.7) 0 2 (0.6) 0 2 (0.5) 0 2 (0.5) 0 2 (0.4)
HELLP syndrome 5 (1.1) 7 (2.5) 0 12 (3.7) 0 12 (3.0) 0 12 (2.8) 0 12 (2.4)
Hepatic hematoma 0 1 (0.4) 0 1 (0.3) 0 1 (0.3) 0 1 (0.2) 0 1 (0.2)
Labor and delivery
Induction of labor 252 (53.5) 205 (73.0) 229 (53.6) 228 (69.9) 199 (54.2) 262 (65.5) 180 (53.3) 284 (65.4) 147 (52.7) 319 (63.8)
Vaginal delivery 312 (66.2) 160 (56.9) 283 (66.3) 189 (58.0) 238 (64.9) 240 (60.0) 220 (65.0) 260 (59.9) 187 (67.0) 294 (58.8)
Spontaneous vaginal delivery 136 (28.9) 38 (13.5) 121 (28.3) 53 (16.3) 99 (27.0) 79 (19.8) 97 (28.7) 81 (18.7) 84 (30.1) 94 (18.8)
MAY 2021 American Journal of Obstetrics & Gynecology

Cesarean delivery 159 (33.8) 121 (43.1) 144 (33.7) 137 (42.0) 129 (35.1) 160 (40.0) 119 (35.2) 173 (39.9) 92 (33.0) 206 (41.2)
Perinatal

OBSTETRICS
Perinatal mortality 43 (9.1) 38 (13.5) 41 (9.6) 40 (12.3) 33 (9.0) 49 (12.3) 31 (9.2) 51 (11.8) 24 (8.6) 59 (11.8)
or major neonatal morbidity
Intrauterine fetal death 1 (0.2) 1 (0.4) 1 (0.2) 1 (0.3) 1 (0.3) 1 (0.3) 0 2 (0.5) 0 2 (0.4)
Neonatal death 0 0 0 0 0 0 0 0 0 0
Ventilation 6 (1.3) 11 (3.9) 5 (1.2) 12 (3.7) 4 (1.1) 13 (3.3) 4 (1.2) 13 (3.0) 3 (1.1) 14 (2.8)

Original Research
RDS 12 (2.5) 10 (3.6) 12 (2.8) 10 (3.1) 10 (2.7) 12 (3.0) 10 (2.9) 12 (2.8) 7 (2.5) 16 (3.2)
Brain injury 2 (0.4) 4 (1.4) 2 (0.5) 4 (1.2) 2 (0.5) 4 (1.0) 2 (0.6) 4 (0.9) 1 (0.4) 5 (1.0)
Sepsis 33 (7.0) 29 (10.3) 32 (7.5) 30 (9.2) 25 (6.8) 38 (9.5) 24 (7.1) 39 (9.0) 19 (6.8) 45 (9.0)
Anemia 1 (0.2) 0 1 (0.2) 0 1 (0.3) 0 1 (0.3) 0 0 1 (0.2)
NEC 1 (0.2) 0 1 (0.2) 0 1 (0.3) 0 1 (0.3) 0 1 (0.4) 0
Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021. (continued)
518.e6
Original Research OBSTETRICS ajog.org

gestational hypertension and z11% have questioned the value of a broad (vs
with PE. Major neonatal morbidity was traditional) definition of PE based on

ACOG, American College of Obstetricians and Gynecologists; CH, chronic hypertension; GH, gestational hypertension; HELLP syndrome, hemolysis, elevated liver enzymes, and low platelet count; ISSHP, International Society for the Study of Hypertension in
Pregnancy; ISSHP-M, ISSHP maternal definition; ISSHP-MF, ISSHP maternal-fetal definition; ISSHP-MF-AI, ISSHP maternal-fetal plus angiogenic imbalance definition; NEC, necrotizing enterocolitis requiring surgery; PE, preeclampsia; RDS, respiratory distress
n¼500 (3.3)
80 (16.0)
122 (24.4)
most commonly due to sepsis and RDS. concerns that a low-risk population is
Neonatal unit admission for
48 hours being identified by the broad definition,
at least at gestational ages preterm.24,25,27
PE

occurred in just over 10% of pregnancies

with gestational hypertension and more However, adverse maternal and neonatal
ISSHP-MF-AI

n¼279 (1.8)

than 15% of those with PE. Babies with a outcome rates have been well above the
29 (10.4)
33 (11.8)

birthweight <10th percentile occurred baseline rates,24,27 similar to our find-

in <20% (and as low as 12%) of preg- ings, suggesting that the use of a broad
GH

nancies with gestational hypertension definition with uteroplacental function,

n¼434 (2.8)

and more than 20% with PE. as defined by EFW, Dopplers, and
69 (15.9)
108 (24.9)

Table 4 shows that the detection rate angiogenic imbalance, is clinically use-
(sensitivity) of PE definitions for adverse ful. In addition, the independent value of
PE

outcomes was higher with all broad routine maternal laboratory test results
definitions, with statistical significance and FGR were recently demonstrated27;
n¼338 (2.2)
38 (11.2)
46 (13.6)
ISSHP-MF

reached for ACOG (for major maternal although the role of headache and visual
morbidity), ISSHP-M (for severe hy- symptoms was not demonstrated, these
GH

pertension and major maternal have been shown to have prognostic

morbidity), ISSHP-MF (for severe hy- value in the absence of laboratory
n¼400 (2.6)

pertension, major maternal morbidity, testing, such as in the self-monitored

65 (16.3)
77 (19.3)
Adverse pregnancy outcomes according to the definitions of gestational hypertension and PE (continued)

and birthweight <10th percentile), and setting in high-income countries or in

ISSHP-MF-AI definitions (for all out- low-resource settings where most
PE

comes). The higher detection rates were women and babies die of PE.
n¼367 (2.4)

achieved with similar true positive rates Most clinical practice guidelines (12 of
42 (11.4)
73 (19.9)
ISSHP-M

(Table 3). 15) identified by systematic review

recommend a broad definition of PE,
GH

Comment based on new-onset hypertension and

Principal findings manifestations including, but not
n¼326 (2.1)
56 (17.2)
69 (21.2)

In a large cohort of women assessed at limited to, new-onset proteinuria.28

35 to 36 weeks’ gestation, the proportion There is widespread agreement for the
PE

of women with PE defined traditionally inclusion of proteinuria (12 of 12

by new-onset hypertension and pro- guidelines), maternal symptoms of
n¼427 (2.8)

teinuria was almost half of that when the headache or visual disturbances (12 of
49 (11.5)
80 (18.7)

Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021.

definition included not only new-onset 12), and abnormal routine laboratory
ACOG

proteinuria but also other maternal testing of low platelet count (11 of 12),
GH

end-organ involvement or uteropla- raised serum creatinine (11 of 12), or

n¼281 (1.8)

cental dysfunction. The higher preva- elevated liver enzymes (12 of 12), but
54 (19.2)
60 (21.4)

lence was associated with improved there is no agreement on how these

identification of women at increased risk should be defined. Our data suggest that
PE

of adverse maternal and perinatal out- the definitions proposed by the ISSHP
comes with similar true positive rates. (rather than the ACOG) may better
n¼471 (3.1)
Traditional

51 (10.8)
88 (18.7)

identify women at risk, such as those

Comparison with published who go on to develop severe hyperten-
GH

literature sion; the ISSHP includes women with

Consistent with our findings, a number organ dysfunctions other than pulmo-
of studies have documented a higher nary edema (eg, eclampsia, stroke) and
Neonatal unit admission
48 h

Data are presented as number (percentage).

Birthweight <10th percentile

prevalence of PE and corresponding less severe perturbations of platelets

lower prevalence of gestational hyper- (<150109/L vs <100109/L), serum
tension and chronic hypertension, using creatinine (
1 mg/dL vs >1.1 mg/dL),
syndrome requiring surfactant.

a broad, rather than traditional, defini- or liver enzymes (aspartate aminotrans-

tion of PE.24e27 Our data confirm that ferase [AST] or alanine aminotransferase
these observations hold true when [ALT] of >40 IU/L rather than
twice
TABLE 3

focused on PE at term, when the largest normal) (Supplemental Table). In addi-

Outcome

proportion of cases occurs. tion, guidelines do not widely endorse

Previous studies of the relationship the inclusion of uteroplacental dysfunc-
between PE definitions and outcomes tion in the broad definition of PE, based

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ajog.org OBSTETRICS Original Research

on any of the following criteria: intra-

uterine fetal death (4 of 12 guidelines),

<.0001

<.0001
P value

.046
.002
.001
FGR (9 of 12), abnormal UA Doppler (3
of 12), angiogenic imbalance (3 of 12),
abruption (2 of 12), oligohydramnios (1

78.7 (122/155)
66.9 (87/130)

73.4 (80/109)
ISSHP-MF-AI

of 12), or abnormal fetal cardiotocog-

71.1 (59/83)
100 (18/18)
raphy (1 of 12). Only angiogenic
(n¼500)

imbalance is defined as a low PlGF or

elevated sFlt-1etoePlGF ratio, but 2
<.0001 guidelines recommend their use as a
“rule-out” test for PE when normal (but
P value

ACOG, American College of Obstetricians and Gynecologists; ISSHP-M, ISSHP maternal definition; ISSHP-MF, ISSHP maternal-fetal definition; ISSHP-MF-AI, ISSHP maternal-fetal plus angiogenic imbalance definition.
.004
.046
.060
.070

not part of the definition when

abnormal)29,30 and 1 guideline as a
“rule-in” test, even in the absence of
70.1 (108/154)
59.2 (77/130)

64.5 (69/107)
62.2 (51/82)

other manifestations of PE.31

100 (18/18)
ISSHP-MF
(n¼434)

Clinical implications
Our findings present an evidence base
for the broad definition of PE. Our data
P value

suggest that compared with a traditional

.013
.046
.117
.213
.064

definition, a broad definition of PE can

better identify women and babies at risk
Detection rate of adverse pregnancy outcomes according to different definitions of preeclampsia

56.2 (73/130)

60.7 (65/107)
51.3 (77/150)

of adverse outcomes, over and above the

59.8 (49/82)
100 (18/18)
ISSHP-M

risks associated with gestational hyper-

(n¼338)

tension. Compared with the ACOG

definition, the more inclusive ISSHP
definition of maternal end-organ
P value

dysfunction seems to be more sensitive.

.449
.046
.875
.890
.349

The addition of the uteroplacental

dysfunction to the broad definition op-
46.1 (59/128)

53.3 (56/105)
46.3 (69/149)

timizes the identification of women and

49.4 (40/81)
100 (18/18)

babies at risk, particularly when angio-

(n¼326)

genic factors are included.

ACOG

Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021.
The P value represents the comparison of the detection rate with the traditional definition of preeclampsia.

Research implications
Our findings should be replicated in a
Reference

population that includes both preterm

pregnancies and uteroplacental
—
—
—
—
—

dysfunction assessed at presentation

40.6 (52/128)

51.4 (54/105)
40.5 (60/148)

with hypertension, with ultrasound,

72.2 (13/18)
46.9 (38/81)
Traditional

Dopplers, and, in particular, angiogenic

(n¼281)

factors. Cost consequences should be

incorporated. Trials should evaluate
whether timed term birth based on a
Perinatal mortality and major morbidity

broad definition of PE, which includes

uteroplacental dysfunction (including
angiogenic imbalance, if available) is
Neonatal unit admission
48 h
Severe maternal hypertension

Birthweight <10th percentile

associated with similar benefits as

Major maternal morbidity

demonstrated for PE based on the

Detection rate, % (n/N)

traditional definition.32

Strength and limitations

TABLE 4

Strengths of our study include the large

Outcome

sample size, unselected nature of women

presenting for a 36-week assessment,
and the prospective, detailed

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Original Research OBSTETRICS
documentation of baseline characteris-
tics, PE criteria, and outcomes. We
investigated the ACOG and ISSHP PE
definitions based on the maternal and
uteroplacental criteria and expanded the
previous definition studied24 by adding 3
criteria: Doppler findings to EFW to
define FGR (instead of EFW <10th
percentile or an antenatal diagnosis of
“intrauterine growth restriction”), in-
trauterine fetal death, and angiogenic
imbalance. Importantly, the women
studied were managed in the United
Kingdom where only a traditional defi-
nition of PE was accepted33 and angio-
genic markers were advised only for
women with suspected PE at <35 0/7
weeks’ gestation.34
A limitation of our data is that all
women enrolled had singleton preg-
nancies, so our results do not necessarily
apply to multiples. We studied a cohort
of women who had reached near-term
gestational age; although our results
may not apply to preterm women, they
are consistent with studies that have
included such women, and most PE oc-
curs at term. We were unable to include
all maternal criteria advocated by the
ISSHP; no information was available on
the clinical criteria of altered mental
status or clonus or the laboratory find-
ings of disseminated intravascular coag-
ulation or hemolysis. We used the 35 0/7
to 36 6/7 weeks’ gestation uteroplacental
assessment to diagnose subsequent new-
onset hypertension as gestational hy-
pertension or PE; although this makes
full use of information collected where
the 36-week scan is routine, it would
have been ideal to have repeat ultraso-
nographic assessment of EFW and
Dopplers or angiogenic balance. How-
ever, we feel that our carryforward of
observations likely underestimated the
prevalence of abnormalities when hy-
pertension developed and thus under-
estimated the strength of the
uteroplacental assessment-outcome
relationship.
Conclusions
Our findings present an evidence base
for the broad definition of PE. Our
data suggest that compared with a
traditional definition, a broad
518.e9 American Journal of Obstetrics & Gynecology MAY 2021
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uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.
definition of PE can better identify
women and babies at risk of adverse
outcomes. Compared with the ACOG
definition, the more inclusive ISSHP
definition of maternal end-organ
dysfunction seems to be more sensi-
tive. The addition of uteroplacental
dysfunction to the broad definition
optimizes the identification of women
and babies at risk, particularly when
angiogenic factors are included. n 14. Webster K, Fishburn S, Maresh M,
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OBSTETRICS
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MAY 2021 American Journal of Obstetrics & Gynecology
Original Research
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Author and article information
From the Fetal Medicine Research Institute, King’s Col-
lege Hospital, London, United Kingdom (Drs Lai, Synge-
laki, and Nicolaides); Department of Women and
Children’s Health, School of Life Course Sciences, Faculty
of Life Sciences and Medicine, King’s College London,
London, United Kingdom (Drs von Dadelszen and Magee);
and Institute of Women and Children’s Health, King’s
Health Partners, London, United Kingdom (Drs von
Dadelszen and Magee).
Received July 21, 2020; revised Sept. 24, 2020;
accepted Nov. 2, 2020.
The authors report no conflict of interest.
This study was supported by a grant from the Fetal
Medicine Foundation (charity number 1037116). The
machine and reagents for the assays were provided by
Thermo Fisher Scientific, Hennigsdorf, Germany. The
funding sources had no involvement in the study design;
collection, analysis, and interpretation of data; writing of
the report; and decision to submit the article for
publication.
Corresponding author: Laura A. Magee, MD. laura.a.
magee@kcl.ac.uk
518.e10
Original Research OBSTETRICS ajog.org

SUPPLEMENTAL TABLE
Definitions of de novo preeclampsia, based on new-onset hypertension with one or more other features
ISSHP
Outcome Traditional ACOG ISSHP-M ISSHP-MF ISSHP-MF-AI
Proteinuriaa C C C C C
Maternal symptoms
Headacheb C C C C
Visual symptomsc C C C C
Maternal signs
Eclampsia - - C C C
Altered mental status - - C C C
Blindness - - C C C
Stroke - - C C C
Clonus - - C C C
Pulmonary edema - C - - -
Maternal routine laboratory tests
Platelet count<150109/L - - C C C
Platelet count<10010 /L 9
- C C C C
DIC - - C C C
Hemolysis - - C C C
Serum creatinine
90 mmol/L or
1 mg/dL - - C C C
Serum creatinine>1.1 mg/dL - C C C C
Serum creatinine doubling in the absence of other renal - C - - -
diseases
AST or ALT
twice normal (
65 IU/L) - C C C C
AST or ALT>40 IU/L - - C C C
Uteroplacental dysfunction
Intrauterine fetal death - - - C C
FGR at screening d
- - - C C
Abnormal angiogenic markers at screening e
- - - - C
The solid dot means that the outcome was included in the definition. The dash means that it was not.
ACOG, American College of Obstetricians and Gynecologists; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DIC, disseminated intravascular coagulation; EFW, estimated fetal
weight; FGR, fetal growth restriction; ISSHP, International Society for the Study of Hypertension in Pregnancy; ISSHP-M, ISSHP maternal definition; ISSHP-MF, ISSHP maternal-fetal definition; ISSHP-
MF-AI, ISSHP maternal-fetal plus angiogenic imbalance definition; PI, pulsatility index; PlGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1.
a
Proteinuria was defined as
2þ by urinary dipstick testing,
30 mg/mmol or 0.3 mg/dL by protein-to-creatinine ratio, or
0.3 g/d by 24-hour urine collection; b Headache was defined by the
ACOG as new-onset headache unresponsive to medication and not accounted for by alternative diagnoses, whereas the ISSHP defined headache as “severe”; c Visual symptoms were not defined by
the ACOG but were defined by the ISSHP as persistent visual scotomata; d FGR was not defined by the ISSHP but was taken here to be the EFW <3rd percentile or EFW at the 3rd to 9th percentile
with abnormal Dopplers, defined as any of uterine artery PI >95th percentile, umbilical artery PI >95th percentile, or middle cerebral artery PI <5th percentile. This definition incorporates the
abnormal umbilical artery Dopplers listed by the ISSHP as a separate criterion; e Angiogenic imbalance was defined as a PlGF <5th percentile or a sFlt-1etoePlGF ratio >95th percentile for
gestational age.
Lai et al. Preeclampsia definitions and their relationship with outcomes. Am J Obstet Gynecol 2021.

518.e11 American Journal of Obstetrics & Gynecology MAY 2021

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